Diabetic peripheral neuropathy (DPN) is a major complication and cause for morbidity and mortality in diabetes mellitus. Despite much effort and investment, there is no clear pathogenic mechanism underlying the disease and therapeutic options are limited to pain management and symptomatic treatments. We propose to test an epigenetic mechanism that will open the door to new treatment options. Studies indicate acerbate (vitamin C) deficiency in tissues of diabetes, caused by the oxidation of acerbate to dehydroascorbic acid (DHA). DHA is then outcompeted (~1:300) by high glucose for cellular uptake leading to intracellular acerbate reduction. Intriguingly, acerbate is essential in axonal myelination by Schwann cells in vitro. Acerbate deficiency also is known to cause peripheral neuropathy in humans and hypomyelination in mice. It is plausible that deficiency in acerbate plays a critical role in demyelinating DPN. Recently, we uncovered a novel function of acerbate in regulating DNA demethylation, which has been validated by others. Ascorbate enhances the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is the major pathway for active DNA demethylation. New insights gleaned from the epigenetic studies led us to develop an unconventional, exceptionally novel hypothesis: The epigenome of Schwann cells is impaired specifically by intracellular ascorbate shortage, leading to demyelinating DPN. Three specific aims are designed to test our hypothesis: (1) To test whether ascorbate deficiency causes demyelinating DPN in vivo; (2) To test whether ascorbate treatment can delay or prevent demyelinating DPN in mice. (3) To test whether an impaired epigenome of Schwann cells caused by ascorbate deficiency underlies demyelinating DPN. Testing this hypothesis will have a significant impact on science and health in the following aspects. (1) Identifying a novel mechanism for DPN and a fresh start for this field to understand pathomechanisms. (2) None of the current rodent models of diabetes mellitus develop demyelinating DPN. Our research will establish a rodent model with demyelination phenotypes, which will be extremely useful to study DPN pathogenesis and to screen drug candidates. (3) This research will have a huge potential impact on clinical care of diabetic patients. Successful prevention of demyelinating DPN in rodent models will implicate the ascorbate pathway to delay or prevent DPN in diabetic patients. (4) This study will be a blueprint for investigations into other diabetic complications such as retinopathy and nephropathy. By testing the exceptionally unconventional hypothesis using innovative approaches, this research will accelerate the knowledge of DPN. Our unique approach has the potential to open up entirely new pathways to a field that has made relatively little progress in the recent decade, especially in terms of translational applications.